Piper was born in Chattanooga, Tennessee, to Bill and Ruth Piper. When he and his older sister were still young, the Pipers moved to Greenville, South Carolina, where he spent the rest of his youth and graduated from Wade Hampton High School.
His father was an itinerant evangelist who actively ministered through international radio and Bible courses until his death in March 6, 2007. Of the fifteen counsels called, Things I Have Learned, of which some go back to his college days, John says:
My father was totally persuaded that wrong means do not lead to right ends. Or, more positively, he was persuaded that living in the right way—that is, doing the right things—are means that inevitably lead to where God wants us to be. This is why he told me, when I asked about God’s leading in my life, “Son, keep the room clean where you are, and in God’s time, the door to the next room will open.”
On January 11, 2006, Piper announced that the month beforehand, he had been diagnosed with prostate cancer. According to a letter sent to his church, he and his doctors believe that the cancer is fully treatable. Piper's reaction to his diagnosis was:
"This news has, of course, been good for me. The most dangerous thing in the world is the sin of self-reliance and the stupor of worldliness. The news of cancer has a wonderfully blasting effect on both. I thank God for that. The times with Christ in these days have been unusually sweet."